Choline supplementation attenuates learning deficits associated with neonatal alcohol exposure in the rat: Effects of varying the timing of choline administration

Abstract

Despite the harmful effects of fetal alcohol exposure, some pregnant women continue to drink alcohol. Thus, it is imperative to pursue safe, effective treatments for children with fetal alcohol spectrum disorders. Using an animal model, our laboratory has demonstrated that choline, an essential nutrient, effectively reduces the severity of some fetal alcohol effects, even when administered after the ethanol insult is complete. The present study investigated whether there is a critical developmental period when choline is most effective in attenuating ethanol’s teratogenic effects. Sprague-Dawley rats were exposed to 5.25 g/kg/day ethanol during the third trimester equivalent brain growth spurt (postnatal days (PD) 4–9) via intubation. A non-intubation control group and a sham intubation control group were included. Following ethanol exposure, pups received subcutaneous injections of saline vehicle or choline chloride (100 mg/kg/day) from PD 11–20, PD 21–30, or PD 11–30. Beginning on PD 45, subjects were tested on a Morris water maze spatial learning task. Performance of both the ethanol-exposed group that did not receive choline and the ethanol-exposed group treated with choline from PD 21–30 was significantly impaired compared to controls during acquisition of the Morris water maze task. Performance of ethanol-exposed groups treated with choline from PD 11–20 or PD 11–30 was intermediate, not differing significantly from any other groups. However, during the probe trial, ethanol exposure produced significant deficits in spatial memory which were mitigated by all choline treatments, regardless of the timing of administration. These findings suggest that choline’s therapeutic window may be very large, or spans across the two developmental periods examined in this study. Importantly, these findings indicate that choline supplementation may effectively reduce some alcohol-related learning impairments, even when administered in later childhood.

Randomized, double-blind, placebo-controlled clinical trial of choline supplementation in school-aged children with fetal alcohol spectrum disorders

“…An examination of the groups separately revealed that small effect sizes and sample sizes would have to have been inordinately large to confidently draw conclusions from the results; in addition, the possibility of a type II error could not be ruled out (achieved power ranged from 0.13 to 0.84). The null findings of this clinical trial were unanticipated because of the strong evidence that has suggested beneficial effects of choline supplementation in animal models of both typical development (39) and prenatal alcohol exposure (3)(4)(5)(6)(7)(8)10). However, this investigation was only one of a few trials to translate the aforementioned animal research to a human clinical trial of choline supplementation in FASDs, and previous studies, at earlier ages, have suggested some positive beneficial effects (13,14).…”

“…Notably, our group was the first, to our knowledge, to examine the effects of a nutritional intervention of choline with the use of a rodent model of FASDs (3). Through a series of studies, we showed that choline reduces the severity of alcohol's adverse effects on behavioral development whether administered perinatally (4,5) or postnatally after alcohol exposure has occurred (3,6,7). Choline mitigates behavioral deficits on tasks that depend on the functional integrity of the hippocampus and prefrontal cortex including spatial learning and memory (8), hyperactivity (8), trace classical conditioning (9,10), and working memory (3).…”

“…Alcohol exposure during pregnancy disrupts fetal development and results in a range of outcomes that are known as fetal alcohol spectrum disorders (FASDs) 7 . Despite known adverse consequences and public health warnings, women continue to consume alcohol during pregnancy (1).…”

The Activation of M1Muscarinic Receptor Signaling Induces Neuronal Differentiation in Pyramidal Hippocampal Neurons

“…These findings may be important for the understanding of the mechanisms behind the beneficial effects of perinatal choline supplementation observed in rodent models of fetal alcohol syndrome (Ryan et al, 2008) and Rett syndrome (Ward et al, 2008), because in both these conditions alterations in the cholinergic system have been proposed (Costa et al, 2001;Ward et al, 2008). In addition, neurite regeneration and repair after neuronal damage may be compromised in certain pathological conditions that cause loss of cholinergic neurons, such as Alzheimer's disease (Bartus et al, 1982).…”

Donepezil Improves Cognitive Function in Mice by Increasing the Production of Insulin-Like Growth Factor-I in the Hippocampus

“…Behavioral testing was conducted as described previously (Ryan et al, 2008). We used a circular pool (150 cm diameter).…”